Onchocerciasis is a non-fatal but disfiguring and blinding disease caused by the filarial worm Onchocerca volvulus. Suramin and Mel W (Trimelarsan) are the only known drugs effective against the adult worms (macrofilaria) of 0. volvulus but both have adverse side effects. A safe and rapidly acting macrofilaricidal drug would alleviate the suffering of not only the 20-40 million people with onchocerciasis but also that of the approximately 250 million people with other filarial and trypanosomal diseases. The overall goal of this application is to synthesize new highly active macrofilaricidal and trypanocidal melaminylthioarsenites (MTAS) that do not induce lethal encephalopathy (EP) in humans as does the existing macrofilaricidal MTAS Mel W. Since EP may be caused by an increase in the arsenic concentration in the choroid plexus and pia resulting from hydrolysis of MTAS, we propose to synthesize new MTAS that are more stable than Mel W from melarsen oxide and aliphatic cationic thiols. We will then test these compounds for their acute toxicity, their trypanocidal activity in mice and macrofilaricidal activity in gerbils, dogs and horses. The arsenic concentration that macrofilaricidal test compounds induce in the choroid plexus and pia of dogs will be measured by atomic absorption and the propensity of these compounds to induce EP will be tested in monkeys. The relative arsenic uptake from MTAS into the parasites and organs of animals will also be assayed in an attempt to determine the mechanism by which arsenicals exert their parasitocidal and toxic effects. We will also prepare the sparingly water soluble suraminates and pamoates of the new MTAS's and test them as to slow-release effects with a view to prophylaxis and one-dose therapy in trypansomiasis and filariasis. We will then prepare the antimony analogues to the best MTAS and test them against T. rhodesiense infection of the mouse, L. carinii infection of the gerbil, and D. immitis infection of the dog. Satisfactory antimony compounds will be prepared as suraminates and pamoates and tested for slow-release effects.